Dopaminergic neurons arising from the ventral tegmental (VTA) area and projecting to the nucleus accumbens (ACb)are key elements of brain circuits that subserve arousal, motivation, and reinforcement. Increased dopamine neurotransmission within this mesoaccumbal pathway are implicated in the reinforcing effects of psychostimulants, alcohol, and other drugs of abuse. [unreadable] [unreadable] Previous studies have shown toluene inhalation produces reinforcing effects in animal models and is abused by humans. Although acute exposure of rats to toluene increases dopamine release in the dorsal striatum similar effects have not been reported in the ACb. These findings have led to the hypothesis that a dopamine-independent mechanism mediates the abuse liability of toluene and other inhalants. Anatomical studies, however, have shown that the ACb consists of two sub-regions termed the shell and the core. Heterogeneity of the VTA and in the responsiveness of VTA dopamine neurons to several drugs of abuse has been reported. [unreadable] [unreadable] We conducted a series of studies to determine whether there are sub-region-specific effects of toluene on neuronal activity in the VTA and ACb. Using in-vitro electrophysiology, we have now shown that behaviorally relevant concentrations of toluene directly stimulates dopamine neurons in the VTA but not in surrounding midbrain regions. Toluene stimulation of VTA neurons persists when synaptic transmission is reduced. Moreover, unlike non-dopamine containing neurons, the magnitude of VTA dopamine neuron firing does not decline during longer exposures designed to emulate 'huffing'. Using dual-probe in-vivo microdialysis to monitor dopamine release, we show that perfusion of toluene directly into the VTA increases dopamine concentrations in the VTA (somatodendritic release) and its terminal projection site, the ACb. The magnitude of the dopamine response to toluene also varied as a function of the VTA sub-region evaluated. These results provide the first demonstration that even brief exposure to toluene increases action potential drive onto mesoaccumbal VTA dopamine neurons, thereby enhancing dopamine transmission in the ACb. The finding that toluene stimulates mesoaccumbal neurotransmission by activating VTA dopamine neurons directly (independently of transynaptic inputs) provide insights into the neural substrates that may contribute to the initiation and pathophysiology of toluene abuse. Importantly, they suggest that the mesoaccumbal pathway may contribute to the abuse of toluene and other inhalants and that targeting this system may be useful for the treatment of toluene abuse. [unreadable] [unreadable] The repeated use of high dose alcohol produces deficits in memory and cognition. These effects have been attributed, at least in part, to alcohol-evoked alterations in hippocampal function and loss of neurons in this region. Kappa opioid receptors (KOPr) and dynorphin, the endogenous KOPr ligand, are enriched in the hippocampus and serve an important function in regulating hippocampal neuronal activity. Our collaborators (NIH and Karolinska Institute Collaborative Program In Postgraduate Education)have obtained evidence that tissue levels of dynorphin, as well as the expression of prodynorphin, the gene encoding dynorphin, are elevated in the hippocampus of human alcoholics. In contrast, other opioid peptides systems are unaltered. KOPr is located on glutamatergic neurons in the hippocampus and modulates glutamate release. Both glutamate and dynorphin have been implicated in the modulation of long-term depression(LTD), a form of synaptic plasticity which is important for learning. Importantly, however, excess glutamate is toxic to neurons and can impair learning and memory. Given the role of the dynorphin/KOPr pathway in synaptic plasticity we have initiated studies to ascertain whether up-regulation of this opioid system contributes to deficits in cognition produced by alcohol and/or alcohol-evoked alterations in hippocampal neurochemistry, we intiated a series of studies to examine whether pharmacological treatments that block the activity of the KOPr/dynorphin system affect hippocampal-dependent memory and glutamate transmission within the CA3 region of the hippocampus. We have used an oral gavage model which enables delivery of high dose alcohol but is not associated with the side-effects associated with the alcohol inhalation model typically used to induced alcohol dependence. Our studies have shown that once daily alcohol (40% v/v ETOH: 10 ml/kg)gavage produces somatic signs of dependence and deficits in learning and memory. Studies using the Morris water maze have revealed that systemic adminsitration of KOPr antagonists following the cessation of repeated, binge alcohol administration prevent memory deficits produced by alcohol. Similar effects are observed in response to the selective blockade of KOPr in the CA3 region indicating that blockade of KOPr in this region is sufficient to prevent the neurotoxic effects of alcohol. Using conventional and quantitative microdialysis (see Chefer et al., 2007 for review), we have found that alcohol-evoked memory impairment is associated with increases in basal and depolarization-evoked glutamate release in CA3 and that these neurochemical changes are prevented by administration of a selective KOPr antagonist. Blood alcohol concentrations are unaffected by KOPr antagonists suggesting that a pharmacokinetic mechanisms underlies the protective effects of KOPr antagonist treatment. On-going studies are determining whether alterations in glutamate transmission produced by alcohol result from a direct effect on glutamatergic neurons; to changes in GABA release which, in turn, modulate excitatory transmission in the hippocampus or to activation of cell death cascades. Results from these studies will enable delineation of the mechanisms by which activation of the KOPr/dynorphin system contributes to alcohol-evoked neurotoxicity.